B7-1/CD80 is known as a bidirectional regulator of T cell activation and tolerance. We previously reported an unanticipated novel role for B7-1 in podocytes as inducible mediator of podocyte injury and proteinuria in humans and animals. B7-1 can be targeted by blocking antibodies such as Abatacept (CTLA4-Ig), which is currently used for the treatment of patients with rheumatoid arthritis. Our novel data obtained with this grant suggest that the anti-proteinuric action of CTLA4-Ig is independent of its inhibitory action on T cell costimulation but stems from a direct effect on podocytes. Our novel data further suggest that the upregulation of B7-1 in podocytes actively contributes to the pathogenesis of proteinuria by altering podocyte structure and function. Most importantly, they offer a rationale for the use o Abatacept as anti-proteinuric treatment. Here we propose to test our central hypothesis that induction of B7-1 expression in podocytes contributes to the pathogenesis of proteinuria by blocking talin mediated 1 integrin activation in podocytes. We further hypothesize that Abatacept/CTLA4-Ig and possible Belatacept prevent proteinuria by blocking B7-1 signaling in podocytes. To test this hypothesis we propose two Specific Aims. The first Aim will define the mechanistic role of B7-1 and the effects of its blockade on podocyte- matrix adhesion. Specific Aim 2 will assess the anti-proteinuric therapeutic potential of B7-1 blockade in mice. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will firmly establish the rationale for a prospective clinical study of B7-1 blockade in patients with proteinuria, including cases of recurrent and non-recurrent FSGS. This should in the long-term enable us to develop novel therapies that tackle proteinuria and glomerulosclerosis by blocking B7-1 signaling in podocytes.